title: Dysregulated NOD2 predisposes SAMP1/YitFc mice to chronic intestinal inflammation.
abstract: Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn's disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.
authors.affiliation: Departments of Medicine and Pathology, and Digestive Health Research Center, Case Western Reserve University, Cleveland, OH 44122.
authors.forename: Daniele
authors.initials: D
authors.lastname: Corridoni
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kodani
authors.forename: Alexander
authors.initials: A
authors.lastname: Rodriguez-Palacios
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
authors.forename: Wei
authors.initials: W
authors.lastname: Xin
authors.forename: Kourtney P
authors.initials: KP
authors.lastname: Nickerson
authors.forename: Christine
authors.initials: C
authors.lastname: McDonald
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Ley
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
authors.forename: Fabio
authors.initials: F
authors.lastname: Cominelli
mesh_terms: D000818:Animals; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000473:pathology; D007079:Ileitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007113:Immunity, Innate; D008806:Mice, Inbred AKR; D008822:Mice, Transgenic; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse